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Kim Nasmyth - One of the best experts on this subject based on the ideXlab platform.

  • division of the nucleolus and its release of cdc14 during anaphase of meiosis i depends on separase spo12 and slk19
    Developmental Cell, 2003
    Co-Authors: Sara B C Buonomo, Mark Petronczki, Frank Uhlmann, Matt Sullivan, Kirsten P Rabitsch, Jorg Fuchs, Stephan Gruber, Attila Toth, Kim Nasmyth
    Abstract:

    Disjunction of maternal and paternal centromeres during meiosis I requires crossing over between homologous chromatids, which creates Chiasmata that hold homologs together. It also depends on a mechanism ensuring that maternal and paternal sister kinetochore pairs attach to oppositely oriented microtubules. Proteolytic cleavage of cohesin's Rec8 subunit by separase destroys cohesion between sister chromatid arms at anaphase I and thereby resolves Chiasmata. The Spo12 and Slk19 proteins have been implicated in regulating meiosis I kinetochore orientation and/or in preventing cleavage of Rec8 at centromeres. We show here that the role of these proteins is instead to promote nucleolar segregation, including release of the Cdc14 phosphatase required for Cdk1 inactivation and disassembly of the anaphase I spindle. Separase is also required but surprisingly not its protease activity. It has two mechanistically different roles during meiosis I. Loss of the protease-independent function alone results in a second meiotic division occurring on anaphase I spindles in spo12delta and slk19delta mutants.

  • polo like kinase cdc5 promotes Chiasmata formation and cosegregation of sister centromeres at meiosis i
    Nature Cell Biology, 2003
    Co-Authors: Rosemary K. Clyne, Vittorio L. Katis, Lea Jessop, Kirsten R Benjamin, Ira Herskowitz, Michael Lichten, Kim Nasmyth
    Abstract:

    During meiosis, two rounds of chromosome segregation occur after a single round of DNA replication, producing haploid progeny from diploid progenitors. Three innovations in chromosome behaviour during meiosis I accomplish this unique division. First, crossovers between maternal and paternal sister chromatids (detected cytologically as Chiasmata) bind replicated maternal and paternal chromosomes together. Second, sister kinetochores attach to microtubules from the same pole (mono-polar orientation), causing maternal and paternal centromere pairs (and not sister chromatids) to be separated. Third, sister chromatid cohesion near centromeres is preserved at anaphase I when cohesion along chromosome arms is destroyed. The finding that destruction of mitotic cohesion is regulated by Polo-like kinases1,2 prompted us to investigate the meiotic role of the yeast Polo-like kinase Cdc5. We show here that cells lacking Cdc5 synapse homologues and initiate recombination normally, but fail to efficiently resolve recombination intermediates as crossovers. They also fail to properly localize the Lrs4 (ref. 3) and Mam1 (ref. 4) monopolin proteins, resulting in bipolar orientation of sister kinetochores. Cdc5 is thus required both for the formation of Chiasmata and for cosegregation of sister centromeres at meiosis I.

  • Disjunction of Homologous Chromosomes in Meiosis I Depends on Proteolytic Cleavage of the Meiotic Cohesin Rec8 by Separin
    Cell, 2000
    Co-Authors: Sara B C Buonomo, Frank Uhlmann, Rosemary K. Clyne, Joerg Fuchs, Josef Loidl, Kim Nasmyth
    Abstract:

    Abstract It has been proposed but never proven that cohesion between sister chromatids distal to Chiasmata is responsible for holding homologous chromosomes together while spindles attempt to pull them toward opposite poles during metaphase of meiosis I. Meanwhile, the mechanism by which disjunction of homologs is triggered at the onset of anaphase I has remained a complete mystery. In yeast, cohesion between sister chromatid arms during meiosis depends on a meiosis-specific cohesin subunit called Rec8, whose mitotic equivalent, Scc1, is cleaved at the metaphase to anaphase transition by an endopeptidase called separin. We show here that cleavage of Rec8 by separin at one of two different sites is necessary for the resolution of Chiasmata and the disjunction of homologous chromosomes during meiosis.

Terry L Orrweaver - One of the best experts on this subject based on the ideXlab platform.

  • 8 chromosome segregation during meiosis building an unambivalent bivalent
    Current Topics in Developmental Biology, 1997
    Co-Authors: Daniel P. Moore, Terry L Orrweaver
    Abstract:

    Faithful chromosome segregation during anaphase requires that stable microtubule connections are established between chromosomes and both spindle poles by metaphase. Bipolar orientation follows an active period of transient connections between the kinctochores and poles, and tension mediated through attachments between the chromosomes stabilizes those bivalents that have connections to opposite poles. This review focuses on how the chromatids are tied together in the bivalent to ensure proper segregation in the two meiotie divisions. Homologs are partitioned in meiosis I, and reciprocal crossovers, cytologically defined as Chiasmata, usually hold the homologs together for this division. The crossovers themselves must be prevented from migrating off the chromatid arms. Binding substances localized to the crossover and sister-ehromatid cohesion distal to the crossover have been proposed to prevent loss of chiasmala. Spontaneous nondisjunction events and mutations that disrupt the maintenance of Chiasmata are analyzed in the context of these models. Homologs that segregate in meiosis I without Chiasmata are briefly discussed. The bivalent must also be constructed so that four chromatids present only two functional kinetochores prior to anaphase I. Cytology and genetic data suggest that the sister kinetochores arc duplicated but constrained to act as a single kinetochore. Additionally, centromeric regions of sister chromatids preserve their cohesion until anaphase II. even as cohesion on the sistcr-chromalid arms is lost at anaphase I. Mutations that specifically disrupt this process are presented. Copyright © 1998 by Academic Press.

  • chromosome segregation during meiosis building an unambivalent bivalent
    Current Topics in Developmental Biology, 1997
    Co-Authors: Daniel P. Moore, Terry L Orrweaver
    Abstract:

    Faithful chromosome segregation during anaphase requires that stable microtubule connections are established between chromosomes and both spindle poles by metaphase. Bipolar orientation follows an active period of transient connections between the kinetochores and poles, and tension mediated through attachments between the chromosomes stabilizes those bivalents that have connections to opposite poles. This review focuses on how the chromatids are tied together in the bivalent to ensure proper segregation in the two meiotic divisions. Homologs are partitioned in meiosis I, and reciprocal crossovers, cytologically defined as Chiasmata, usually hold the homologs together for this division. The crossovers themselves must be prevented from migrating off the chromatid arms. Binding substances localized to the crossover and sister-chromatid cohesion distal to the crossover have been proposed to prevent loss of Chiasmata. Spontaneous nondisjunction events and mutations that disrupt the maintenance of Chiasmata are analyzed in the context of these models. Homologs that segregate in meiosis I without Chiasmata are briefly discussed. The bivalent must also be constructed so that four chromatids present only two functional kinetochores prior to anaphase I. Cytology and genetic data suggest that the sister kinetochores are duplicated but constrained to act as a single kinetochore. Additionally, centromeric regions of sister chromatids preserve their cohesion until anaphase II, even as cohesion on the sister-chromatid arms is lost at anaphase I. Mutations that specifically disrupt this process are presented.

Peter L Borst - One of the best experts on this subject based on the ideXlab platform.

  • a mutation in the endonuclease domain of mouse mlh3 reveals novel roles for mutlγ during crossover formation in meiotic prophase i
    PLOS Genetics, 2019
    Co-Authors: Melissa Toledo, Vandana Raghavan, Xianfei Sun, Miguel A Brienoenriquez, Stephen K Gray, Jeffrey Pea, Carolyn R Milano, Anita Venkatesh, Lekha Patel, Peter L Borst
    Abstract:

    During meiotic prophase I, double-strand breaks (DSBs) initiate homologous recombination leading to non-crossovers (NCOs) and crossovers (COs). In mouse, 10% of DSBs are designated to become COs, primarily through a pathway dependent on the MLH1-MLH3 heterodimer (MutLγ). Mlh3 contains an endonuclease domain that is critical for resolving COs in yeast. We generated a mouse (Mlh3DN/DN) harboring a mutation within this conserved domain that is predicted to generate a protein that is catalytically inert. Mlh3DN/DN males, like fully null Mlh3-/- males, have no spermatozoa and are infertile, yet spermatocytes have grossly normal DSBs and synapsis events in early prophase I. Unlike Mlh3-/- males, mutation of the endonuclease domain within MLH3 permits normal loading and frequency of MutLγ in pachynema. However, key DSB repair factors (RAD51) and mediators of CO pathway choice (BLM helicase) persist into pachynema in Mlh3DN/DN males, indicating a temporal delay in repair events and revealing a mechanism by which alternative DSB repair pathways may be selected. While Mlh3DN/DN spermatocytes retain only 22% of wildtype Chiasmata counts, this frequency is greater than observed in Mlh3-/- males (10%), suggesting that the allele may permit partial endonuclease activity, or that other pathways can generate COs from these MutLγ-defined repair intermediates in Mlh3DN/DN males. Double mutant mice homozygous for the Mlh3DN/DN and Mus81-/- mutations show losses in Chiasmata close to those observed in Mlh3-/- males, indicating that the MUS81-EME1-regulated crossover pathway can only partially account for the increased residual Chiasmata in Mlh3DN/DN spermatocytes. Our data demonstrate that mouse spermatocytes bearing the MLH1-MLH3DN/DN complex display the proper loading of factors essential for CO resolution (MutSγ, CDK2, HEI10, MutLγ). Despite these functions, mice bearing the Mlh3DN/DN allele show defects in the repair of meiotic recombination intermediates and a loss of most Chiasmata.

  • a mutation in the endonuclease domain of mouse mlh3 reveals novel roles for mutlγ during crossover formation in meiotic prophase i
    bioRxiv, 2019
    Co-Authors: Melissa Toledo, Vandana Raghavan, Xianfei Sun, Miguel A Brienoenriquez, Stephen K Gray, Jeffrey Pea, Anita Venkatesh, Lekha Patel, Peter L Borst, Eric Alani
    Abstract:

    During meiotic prophase I, double strand breaks (DSBs) initiate homologous recombination leading to non-crossovers (NCOs) and crossovers (COs). In mouse, 10% of DSBs are designated to become COs, primarily through a pathway dependent on the MLH1-MLH3 heterodimer (MutLγ). Mlh3 contains an endonuclease domain that is critical for resolving COs in yeast. We generated a mouse Mlh3DN allele harboring a mutation within this conserved domain that is predicted to generate a protein that is catalytically inert. Mlh3DN/DN males, like fully null Mlh3-/- males, have no spermatozoa and are infertile, yet spermatocytes have normal DSBs and undergo normal synapsis events in early prophase I. Unlike Mlh3-/- males, however, mutation of the endonuclease domain within MLH3 permits normal loading and frequency of MutLγ in pachynema. However, DSB repair and CO designation factors persist in Mlh3DN/DN males, indicating a temporal delay in repair events. While Mlh3DN/DN spermatocytes retain only 22% of wildtype Chiasmata counts, this frequency is greater than observed in Mlh3-/- males (10%), suggesting that the allele may be partially functional or that other pathways can generate COs from these MutLγ-defined repair intermediates in Mlh3DN/DN males, with evidence favoring the latter option. Double mutant mice that are homozygous for the Mlh3DN/DN mutation along with a null allele of Mus81, show losses in Chiasmata approaching levels observed in Mlh3-/- males, suggesting that the MUS81-EME1-regulated crossover pathway accounts for some of the increased residual Chiasmata observed in the Mlh3DN/DN spermatocytes. These results demonstrate that an intact MLH3 endonuclease domain is essential for most COs in mammalian meiosis, and that an endonuclease-impaired MutLγ retains the ability to facilitate the recruitment of other repair pathways, including MUS81-EME1.

  • mutation of mlh3 endonuclease motif reveals integration between crossover pathways in mammalian meiosis
    bioRxiv, 2019
    Co-Authors: Melissa Toledo, Vandana Raghavan, Xianfei Sun, Miguel A Brienoenriquez, Stephen K Gray, Jeffrey Pea, Anita Venkatesh, Lekha Patel, Peter L Borst, Eric Alani
    Abstract:

    SUMMARY The MLH1-MLH3 complex is essential for crossing over in mammalian meiosis. We generated a mutation in mouse MLH3 that disrupts its conserved endonuclease domain and show that it disrupts crossing over in a manner distinct from the null, but also results in male infertility. ABSTRACT During meiotic prophase I, double strand breaks (DSBs) initiate homologous recombination leading to non-crossovers (NCOs) and crossovers (COs). In mouse, 10% of DSBs are designated to become COs, primarily through a pathway dependent on the MLH1-MLH3 heterodimer (MutLγ). Mlh3 contains an endonuclease domain that is critical for resolving COs in yeast. We generated a mouse Mlh3DN allele harboring a mutation within this conserved domain that is predicted to generate a protein that is catalytically inert. Mlh3DN/DN males, like fully null Mlh3−/− males, have no spermatozoa and are infertile, yet spermatocytes have normal DSBs and undergo normal synapsis events in early prophase I. Unlike Mlh3−/− males, however, mutation of the endonuclease domain within MLH3 permits normal loading and frequency of MutLγ in pachynema. However, DSB repair and CO designation factors persist in Mlh3DN/DN males, indicating a temporal delay in repair events. While Mlh3DN/DN spermatocytes retain only 22% of wildtype Chiasmata counts, this frequency is greater than observed in Mlh3−/− males (10%), suggesting that the allele may be partially functional or that other pathways can generate COs from these MutLγ-defined repair intermediates in Mlh3DN/DN males, with evidence favoring the latter option. Double mutant mice that are homozygous for the Mlh3DN/DN mutation along with a null allele of Mus81, show losses in Chiasmata approaching levels observed in Mlh3−/− males, suggesting that the MUS81-EME1-regulated crossover pathway accounts for some of the increased residual Chiasmata observed in the Mlh3DN/DN spermatocytes. These results demonstrate that an intact MLH3 endonuclease domain is essential for most COs in mammalian meiosis, and that an endonuclease-impaired MutLγ retains the ability to facilitate the recruitment of other repair pathways, including MUS81 -EME1.

Genevieve Leducrobert - One of the best experts on this subject based on the ideXlab platform.

  • multiple origins of sex chromosome fusions correlated with chiasma localization in habronattus jumping spiders araneae salticidae
    Evolution, 2013
    Co-Authors: Wayne P Maddison, Genevieve Leducrobert
    Abstract:

    Entelegyne spiders rarely show fusions yielding neo-Y chromosomes, which M. J. D. White attributed to a constraint in spiders, namely their proximal chiasma localization acting to upset meiotic segregation in males with fusions. Of the 75 taxa of Habronattus and outgroups studied, 47 have X1 X2 0 sex chromosomes in males, 10 have X1 X2 Y, 15 have X1 X2 X3 Y, 2 have X0, and one has both X1 X2 0 and X1 X2 X3 Y. Chromosome numbers and behavior suggest neo-Ys formed by an autosome-X fusion to make X1 X2 Y, with a second fusion to an autosome to make X1 X2 X3 Y. Phylogeny shows at least 8-15 gains (or possibly some losses) of neo-Y (i.e., X-autosome fusions), a remarkable number for such a small clade. In contrast to the many X-autosome fusions, at most one autosome-autosome fusion is indicated. Origins of neo-Y are correlated significantly with distal localization of Chiasmata, supporting White's hypothesis that evolution of neo-Y systems is facilitated by looser pairing (distal Chiasmata) at meiosis. However, an alternative (or contributing) explanation for the correlation is that X-autosome fusions were selected to permit isolation of male-favored alleles to the neo-Y chromosome, aided by distal Chiasmata limiting recombination. This intralocus sexual conflict hypothesis could explain both the many X-autosome fusions, and the stunning complexity of male Habronattus courtship displays.

Ayumu Yamamoto - One of the best experts on this subject based on the ideXlab platform.

  • Chiasmata promote monopolar attachment of sister chromatids and their co segregation toward the proper pole during meiosis i
    PLOS Genetics, 2011
    Co-Authors: Yukinobu Hirose, Ren Suzuki, Tatsunori Ohba, Yumi Hinohara, Hirotada Matsuhara, Yuta Itabashi, Hiroshi Murakami, Masashi Yoshida, Ayumu Yamamoto
    Abstract:

    The chiasma is a structure that forms between a pair of homologous chromosomes by crossover recombination and physically links the homologous chromosomes during meiosis. Chiasmata are essential for the attachment of the homologous chromosomes to opposite spindle poles (bipolar attachment) and their subsequent segregation to the opposite poles during meiosis I. However, the overall function of Chiasmata during meiosis is not fully understood. Here, we show that Chiasmata also play a crucial role in the attachment of sister chromatids to the same spindle pole and in their co-segregation during meiosis I in fission yeast. Analysis of cells lacking Chiasmata and the cohesin protector Sgo1 showed that loss of Chiasmata causes frequent bipolar attachment of sister chromatids during anaphase. Furthermore, high time-resolution analysis of centromere dynamics in various types of chiasmate and achiasmate cells, including those lacking the DNA replication checkpoint factor Mrc1 or the meiotic centromere protein Moa1, showed the following three outcomes: (i) during the pre-anaphase stage, the bipolar attachment of sister chromatids occurs irrespective of chiasma formation; (ii) the chiasma contributes to the elimination of the pre-anaphase bipolar attachment; and (iii) when the bipolar attachment remains during anaphase, the Chiasmata generate a bias toward the proper pole during poleward chromosome pulling that results in appropriate chromosome segregation. Based on these results, we propose that Chiasmata play a pivotal role in the selection of proper attachments and provide a backup mechanism that promotes correct chromosome segregation when improper attachments remain during anaphase I.